Abstract
Cognitive impairment (CI) is important to be detected in patients living with MS due to several following reasons. First, even if CI is often underestimated by patients and physicians, patients with MS are frequently cognitively impaired, and cognitive deficits could be observed in different stages and phenotypes of MS. Information processing speed has been proposed to be the main cognitive domain impaired in patients with MS. It appears crucial to take cognition into account in the clinical practice and to perform neuropsychological assessment with dedicated tools. Concretely, CI could affect daily, familial, social, and vocational activities and alter the health-related quality of life of patients with MS. The pathophysiology of CI is still not completely elucidated, and this research field gains interest. Both focal and diffuse white and gray matter damage participate in explaining CI in MS. At the early stage of the disease, CI could be used as a prognostic marker and could contribute in defining the severity of the pathology. Consequently, detecting CI could influence the therapeutic strategy in MS and studies investigating specific treatment are in progress.
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Keywords
- Cognition
- Neuropsychological battery
- Information processing speed
- Episodic memory
- Executive function
- Prognostic
- Cognitive compensation
- Cognitive reserve
- Cognitive remediation
Introduction
The nature, frequency, severity, and evolution of cognitive impairment (CI) seen in patients with multiple sclerosis (MS) will be explained in the first part of this chapter. Then, the neuropsychological (NP) batteries used in MS will be described and each NP test will be detailed. In the third part, the consequences of CI will be addressed. Concerning the pathophysiology of CI, imaging and histopathological data will be reported in order to illustrate anatomical substrates underlying CI in MS. Cognitive compensation and cognitive reserve will be approached in order to explain the clinico-radiological paradox and heterogeneity seen in patients with MS. Based on these correlates, the prognostic value of CI in MS will be demonstrated in the fifth part. Finally, therapeutic options will be discussed for managing CI in patients with MS.
Nature, Frequency, Severity, and Evolution of Cognitive Deficits
Cognitive dysfunction in patients with MS has long been underestimated both by patients and physicians in part due to the fact that cognitive deficits are invisible compared to motor or cerebellar symptoms, for instance. This topic has progressively gained interest in research and in clinical practice, and there is now increasing evidence that CI is common in MS [1, 2].
Nature of Cognitive Deficits
Information processing speed (IPS) is commonly reduced in patients with MS. There are some controversial data concerning the respective contribution of IPS and working memory on cognitive functioning. One approach is to consider that impairment in IPS could affect primarily the functioning of the other cognitive domains. Thus, patients with MS could perform normally if they have enough time at least in the beginning of the disease. Some studies have supported this theory suggesting that IPS impairment is a central and key cognitive defect in this disease [3, 4]. Another approach is to consider the mediating role of working memory that has been recently proposed in a study performed in patients with early relapsing-remitting MS (RRMS) [5]. Besides this important deficit in IPS, episodic memory is frequently impaired in MS [6, 7]. In a mixed sample of patients with MS, impairment in verbal and visuospatial episodic memories has been reported [7]. Poor performances were found at both the immediate and delayed recall suggesting impairment in the coding of the information. Impairment of executive functions is also an important cognitive deficit occurring during the disease with a negative impact [7].
Frequency of Cognitive Deficits
It has been recognized that CI is frequent in MS and could be identified in all types and stages of MS [1, 2, 8]. The frequency rates of CI in patients with MS could vary from 35 to 70 % at both early and late stages of clinically definite MS (CDMS) [6, 8]. On one hand, a comprehensive NP battery was administered to 100 community-based heterogeneous patients with MS, and 43 % of CI was detected in this pivotal study reported by Rao et al. [6]. One the other hand, previous university-based medical centers have reported that cognitive deficits were present in 54–65 % in patients with MS [9–11]. Recent studies have focused on more homogeneous sample of patients with MS. Thus, in a cohort of 44 early relapsing-remitting MS (RRMS), CI was detected in 45 % of patients within six months after MS diagnosis (defined by at least two abnormal NP tests below the fifth percentile compared to matched healthy controls (HCs)) [12]. In the same stage and using the same definition, an Italian multicentric study has reported 34.9 % of CI in a large cohort of more than 500 early RRMS patients [13]. In the same sample using a more stringent definition for CI (at least three abnormal NP tests below the fifth percentile compared to matched HCs), only 19.5 % of patients were classified as having CI. In contrast, at later stages of the disease but with mild disability assessed by the Expanded Disability Status Scale (EDSS), CI was observed in 45 % of a group of 163 patients who have been so-called benign MS (BMS) defined by a score of EDSS less or equal to 3.0 after at least 15 years of disease duration [14]. In fact, the real proportion of BMS patients could be overestimated through the lack of systematic cognitive assessment in MS in practice.
It is noteworthy that the frequency of CI reported in studies including patients with MS is basically heterogeneous. This is mainly due to methodological aspects. Indeed, the estimation of CI could vary in relation to the sample composition and could depend on the norms used for the interpretation of the results (published normative data or own sample of HCs matched to the studied patients for age, sex, and educational level). Moreover, the determination of CI depends on the method and the chosen definition used for classifying patients with or without CI. In fact, this comes from a lack of consensus on how to define CI in MS. Thus, the questions remain concerning the minimal numbers of abnormal NP tests or cognitive domains before classifying a patient as cognitively impaired. Another approach is to use Z-scores with the following formula for each NP score: “MS patient’s score - mean value of their own matched HCs group)/SD of the matched HCs.” Then, a chosen cut-off could be applied to Z-score per NP test in order to define a cognitively impaired patient for a given NP test. Besides, there is no strong consensus on the cut-off for defining an abnormal performance. The data are not homogeneous across the studies and could vary between 1 standard deviation (SD) to 2 SD when comparing the scores or Z-scores of patients to matched HCs. Considering a threshold of 1.64 SD (equivalent to the fifth percentile) could be a good compromise. This important question has been addressed in an interesting paper comparing the criteria of CI in MS studies according to inclusion criteria of patients (early versus late stages of MS) [15]. Three classification strategies have been individualized among 20 approaches used for classifying CI in MS and were applied differently depending on the stage of MS. One strategy is based on the number of abnormal NP tests, another on the determination of a composite score, and the last is a combination of the first two. Even if most of the researchers applied the first strategy, they used different cut-off for defining an abnormal score for each NP test. Nevertheless, it appears that the cut-off on about 20 % of abnormal tests with a score below the fifth percentile is used in most of the cases. One of the conclusions is that the choice of the classification appears to be driven by the sample of patients (early versus late stage of MS). In studies done at the early stage of the disease, a more liberal definition is mainly chosen, whereas a more stringent and conservative definition is applied at later stage of the pathology.
The relationship between the frequency of CI and disease duration has been questioned. After the first clinical event suggestive of MS called clinically isolated syndrome (CIS), there is increasing evidence that cognitive deficits could be present even if they could be detected in a lower frequency than those observed in RRMS (from 25 to 30 %). Additionally, the deficits are more focused in CIS than in later stage of MS [10, 16–21], and the most impaired cognitive domains are IPS, working memory, attention, and verbal fluency. Moreover, at a preclinical stage suggestive of MS called radiologically isolated syndrome (RIS), the same pattern of cognitive deficits has been observed as previously described in one third of the sample (from 27.6 [22] to 30.8 % [23].
In contrast to RRMS, little information is available concerning cognitive dysfunction in progressive MS patients [24–30]. In one study comparing CIS, RRMS, and progressive MS divided by primary and secondary progressive MS (PPMS and SPMS, respectively), a continuum has been demonstrated in terms of frequency of cognitively impaired patients taking into account the scores of each NP test included in the battery [29]. These data suggest that there is an increase of CI from CIS to RRMS to SPMS.
In contrast, the actual frequency and the nature of CI in patients with PPMS are not fully established due to some methodological limitations of studies including heterogeneous samples of patients with MS. Indeed, patients with RRMS and those with PPMS are frequently different in terms of demographics findings such as age and gender, so appropriate control groups are needed for correct matching a priori. One study has specifically taken these differences into account by including more than 400 HCs in order to match adequately patients and controls for age, sex, and educational level [30]. It has been demonstrated that patients with PPMS had more diffuse CI than those with RRMS form. IPS was the most frequently impaired cognitive domain in both PPMS and RRMS patients, and the two cognitive domains, which differed between these two types of MS, were verbal episodic memory and executive function with respect to the frequency.
Severity of Cognitive Impairment
Few studies have directly compared the severity of CI in different types of MS [24–30]. In the study comparing 415 HCs, 60 RRMS patients, and 41 PPMS patients, one important finding was the difference of CI in terms of severity between these two types of MS [30]. Patients with PPMS had not only more diffuse CI but also more severe cognitive deficits than patients with RRMS especially in verbal episodic memory and working memory. Notably, patients with PPMS had more pronounced CI than patients with RRMS, even after controlling for physical disability, as assessed using the EDSS score, with the same mean disease duration.
Evolution of Cognition in MS
Whereas there are a lot of cross-sectional studies on cognition in MS, few studies had a longitudinal design that could investigate the progression of cognitive deficits in patients with MS. One should be cautious in the interpretation of the results in that type of studies due to inter-patient variability. The follow-up period varies in range from 1 to 18 years [31–38]. The course of cognitive performance in patients with MS is partly contradictory, as some studies have reported the preservation of cognitive functioning, whereas others have observed a mild to moderate cognitive decline over time in MS [39]. In fact, methodological factors often limit the direct comparison of the results, such as the difference in the composition of studied sample, the length of the follow-up period, and the definition chosen for cognitive decline over time. In one 3-year follow-up study, patients with MS were divided into two groups – a group of cognitively preserved (CP) and a group of cognitively impaired patients at baseline – with the same level of physical disability [32]. The patients from the first group remained cognitively stable in the majority of cases, except for one third of patients who exhibited slight deterioration. In contrast, more than two thirds of the patients considered impaired at baseline presented a cognitive decline in many NP tests. These findings suggest that early cognitive decline could predict further widespread and progressive deterioration, whereas patients with intact cognitive performances might remain stable. The relative short-term of follow-up could explain the absence of cognitive decline in the first group of patients. In a 10-year longitudinal study of 45 MS patients, cognitive deterioration was reported in all patients, even in patients without initial CI [33]. During the first 7 years after MS diagnosis, 40.9 % of cognitively impaired patients and 59.1 % of CP patients showed deterioration in memory domains, whereas almost one third of patients (22.7 %) – including both patients with and without CI – presented IPS deterioration [40]. One recent study has reported the cognitive performances of patients included in one phase III clinical trial of intramuscular interferon beta 1a [38]. One advantage of this study is the long period of follow-up since the last assessment was performed 18 years after the inclusion. A cognitive deterioration has been observed and it concerns mainly IPS domain. Interestingly, the decline over time of IPS was found more frequently in the unimpaired patients than the impaired group of patients at baseline. Looking at the early stage of the disease, it has been reported that the proportion of cognitively impaired patients could almost double in the years following the CIS (from 29 % at the CIS stage to 54 % 5 years later) [41]. In one-year follow-up study, the occurrence of isolated cognitive relapses (ICRs) was associated with poor cognitive performance suggesting ICRs as a factor for cognitive decline in MS [42]. The ICRs were defined as a transient reduction of the Symbol Digit Modalities Test (SDMT) [43] score of at least four points during the relapse in comparison to pre- and post-relapse assessment. Notably, ICRs were not reported by patients who did not feel any change either in cognition, mood, or fatigue and were detected only by objective evaluation.
How to Assess Cognitive Function
One challenging question is how to assess cognitive function in patients with MS in clinical practice and in research activities. The gold standard consists of the administration of a comprehensive NP battery performed by a qualified practitioner (neuropsychologist, neurologist). Thus, the most commonly used NP battery in MS is the Brief Repeatable Battery of Neuropsychological Tests (BRB-N) proposed by Rao et al. [44], which includes tests of attention, IPS, episodic verbal and visuospatial memory, and verbal fluency (Tables 16.1 and 16.2). A French NP battery has been proposed after modifying some NP tests and adding others in order to explore executive functions in particular [45] (Table 16.1). In 2002, a group of experts proposed a new battery called the Minimal Assessment of Cognitive Function in MS (MACFIMS) based on a consensus approach [46] (Table 16.1). The aim of that battery is to cover five cognitive domains commonly impaired in MS such as IPS/working memory, learning and memory, executive function, visual-spatial processing, and language. In parallel, it is worth to mention that confounding factors like fatigue, depression, and anxiety must be assessed as they could influence cognitive performance.
Another option to assess cognition is the administration of self-questionnaires. Thus, one auto-questionnaire called the MS Neuropsychological Screening Questionnaire (MSNQ) has been proposed for patients and informants [47]. Unluckily, the cognitive self-report complaints do not reflect cognitive test performance in MS, but are more likely associated with depressive symptoms [47–49]. Nevertheless, fulfilling this type of questionnaires by informants could be helpful as it has been considered more reliable than self-reports fulfilled directly by patients with MS [47, 49].
One limitation of the use of comprehensive NP is that its administration is not feasible everywhere in clinical practice and it is time consuming. So, the issue has been to determine which relevant NP tests could be used minimally for detecting cognitive dysfunction in MS and for selecting patients who require additional evaluation from an expert. The SDMT [43] has been proposed as a good candidate for detecting CI in comparison to other NP tests in early RRMS patients [48] and in a mixed sample of patients with MS (both RRMS and SPMS patients) [50]. This test described in Table 16.2 is part of both the BRB-N and MACFIMS batteries. Notably, it is associated with a good reliability in several assessments [51, 52]. Thus, this IPS test has been chosen to be part of the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) which consists of the minimal cognitive evaluation required for patients with MS [53] (Table 16.3). Nevertheless, one weakness of the SDMT is its practice effect, and a computerized screening cognitive test (CSCT) [54], detailed in Table 16.2, has been proposed for limiting this. The CSCT was associated with a good accuracy for assessing IPS in patients with MS in comparison to other IPS tests included in the test of attentional performance (TAP) [57]. In addition to the SDMT, it has been recommended by this group of experts to include the California Verbal Learning Test-Second Edition [58] to assess episodic verbal memory and the Brief Visuospatial Memory Test-Revised [59] to explore episodic visuospatial memory as memory dysfunction occurs frequently in MS too (Tables 16.2 and 16.3). The application of this brief cognitive assessment is ongoing in international research studies in MS.
Consequences of Cognitive Impairment
Cognitive impairment could affect different aspects in the lives of persons with MS. There are some direct and indirect consequences in terms of daily activities, social function, leisure activities, and interpersonal relationships with family, partners, and friends [1, 2, 60]. Moreover, cognitively impaired patients were more unemployed than cognitively unimpaired patients in several studies [60–62]. Importantly, early cognitive status, independently to physical disability, contributed to the vocational status change in a cohort of patients included after the diagnosis of MS and followed during seven years [62]. In particular, IPS impairment could predict this change, and cognitive deterioration was associated with both the vocational status at the end of the follow-up and its change over the first seven years after the diagnosis.
There is a negative impact on mood too and CI could interfere in self-esteem feeling and copying strategy. In general, CI could alter life satisfaction and the health-related quality of life [60, 62–67]. Driving capacities could be compromised depending on the extent and the severity of CI. In terms of the general treatment of the disease, the presence of CI does modify medical decisions and medication adherence. The management of CI and rehabilitation programs are further detailed in part VI of this chapter.
Pathophysiology of Cognitive Impairment
The pathological substrate of CI in patients with MS is not completely understood. Structural and functional imaging and histopathological studies have provided data suggesting the role of both focal and diffuse brain damage within and outside MS lesions in white and gray matter (WM and GM, respectively) [Review in 68–70].
The first approach is to consider simple imaging parameters such as the distribution, amount, and the extent of focal WM lesions. White matter lesion volume has been found greater in cognitively impaired than in CP patients with MS in many studies [68, 70], but there are only mild to moderate correlation with CI. These modest associations between WM lesions and CI in MS could be explained by the fact that T2 hyperintensities reflect heterogeneous pathologic substrates, including edema, inflammation, demyelination, remyelination, gliosis, axonal loss, and there is a lack of pathological specificity. More importantly, specific locations have been highlighted, and lesions in corpus callosum have been associated with CI in patients with MS [71]. Moreover, some clinical and imaging studies have suggested the role of the cerebellum in CI and in particular in IPS impairment in MS [72–75]. Secondly, it appears interesting to focus on diffuse brain damage and in particular to study the so-called normal-appearing white matter or brain tissue (NAWM and NABT, respectively). In a cross-sectional study, diffuse brain damage assessed by magnetization transfer imaging (MTI) was associated with early CI in patients recently diagnosed with RRMS [12]. These results were replicated in other studies and especially in sample including patients after the first clinical demyelinating event suggestive of MS [76]. Cognitive impairment could be the consequence of brain disconnection due to these abnormalities located in WM tracts. Diffusion tensor imaging (DTI) protocols have allowed to study different metrics including fractional anisotropy in the whole WM skeleton using a tract-based spatial statistic analysis [77, 78] or in specific WM tracts [79] showing the relative contribution of lesional and non-lesional WM in cognitive performance in patients with MS. Several functional MRI (fMRI) studies have also provided interesting findings in patients with MS without CI and with CI and illustrated cortical reorganization that is different according to the stage of MS [68–70]. Brain compensatory mechanisms have been found at early stage of the disease [74, 80, 81], and functional disconnection may affect these mechanisms needed to overcome focal and diffuse structural damage occurring during the disease. There are only few longitudinal studies that included early RRMS patients with several cognitive and MRI evaluations with a long-term follow-up. In one 7-year follow-up study, MRI parameters reflecting the extent and the severity of the diffuse damage in NABT and the net consequence of the diffuse brain damage assessed by atrophy measurements (whole brain and central atrophy) more strongly predicted CI in RRMS patients than visible lesions in the WM [40].
Besides WM, there is increasing interest concerning the damage within the GM for explaining CI in MS [82]. Cortical lesion volume has been found to be higher in cognitively impaired than CP patients with MS [83]. Once again, lesions in specific locations have been considered clinically relevant and were associated with CI in patients with MS. In particular, the regions of interest are deep GM structures such as the thalamus and other basal ganglia and the hippocampus [68–70]. Moreover, brain atrophy appears as a better predictor of cognitive deterioration in patients with MS than WM lesion load [68]. In particular, GM atrophy might play a significant role in the physiopathology of CI in MS, and both cortical and subcortical atrophy have been significantly correlated to CI in patients with MS [68, 82]. Some studies have investigated the role of thalamic atrophy in CI in patients with MS and this topic gains interest [70, 82]. Moreover, a few studies have focused on the hippocampus showing the role of its atrophy mainly in memory impairment in patients with MS [70, 84].
Finally, structural and functional approaches could be combined in order to better explore cognitive functions in patients with MS. A functional disconnection between GM structures at least, partially secondary to damage located in specific WM areas, has been suggested as one of the most important mechanisms leading to CI in MS. A promising method could be to investigate resting-state connectivity. In early MS patients, both structural damage and resting-state functional connectivity changes in brain networks have been investigated [85]. Interestingly, when comparing the different effect sizes of MRI metrics, the highest value was found among the functional connectivity measurements. Moreover, atrophy in one specific area, namely, the posterior cingulate cortex (PCC), was the only predictor of the functional correlation between the medial prefrontal cortex and the PCC. Moreover, the presence of brain and cognitive reserve could attenuate the negative effect of the cumulative brain damage on cognitive performance in patients with MS [86–88]. An interesting longitudinal study including patients after the first clinical demyelinating event (CIS) was performed to investigate the correlates of the evolution of cognitive scores with the change of MRI parameters within 2-years of follow-up [89]. Surprisingly, no significant differences were observed between baseline cognitive status and both baseline and change of MRI metrics in this CIS cohort. One of the explanations could be the presence of cognitive reserve present at this very early stage of the disease.
Few studies have focused only on patients with PPMS. Focal and diffuse WM damage and GM pathology have been reported as significant predictors of cognitive performance in IPS, attention, and executive function in a 5-year follow-up study including 31 patients with PPMS [90]. Additionally, in an immunohistochemical study of postmortem brains of 26 patients with PPMS, a generalized diffuse meningeal inflammation was reported [91]. This confined inflammation might play a significant role in the pathogenesis of cortical GM lesions and contribute to the clinical disability in these patients.
Prognostic Factor
Physical disability and CI could occur independently from each other during the course of the disease, and patients could present CI even before the manifestation of physical symptoms. Aforementioned, patients who are so-called BMS could have CI despite of a low EDSS supporting the need to detect cognitive deficits for evaluating the severity of the disease. Notably, it has been proposed a modification of the definition of BMS in order to include cognitive assessment [92]. The relationship between physical disability and cognition has been questioned in MS. Significant correlations between the EDSS score and cognitive test performances have been reported [93, 94]. Even if modest relationships are typically observed between CI and physical disability in MS, the majority of these results primarily concern the measurement of IPS [94–97]. These data highlight the prognostic value of IPS impairment that is considered as a central defect in MS. In a 7-year longitudinal study, the cognitive deterioration was correlated with MRI parameters reflecting mainly the initial brain diffuse axonal injury and its early change within the first two years [40]. These results support the role of early central atrophy in CI in patients with RRMS and in particular its correlation with IPS decline in early MS. The early identification of IPS impairment could be a relevant marker of early central atrophy that has been used for predicting the progression of the disability assessed through changes in EDSS [98].
Management of Cognitive Impairment
Medications: Disease-Modifying Drugs and Symptomatic Treatment
Aforementioned, cognitive status should be included in treatment decisions independently of physical disability as it represents a marker for disease severity and progression. Nevertheless, the historical clinical trials did not take into account these data in defining the efficacy of treatments in MS. Cognitive functions have been evaluated mainly in post hoc analysis of the first clinical trials of disease-modifying drugs in MS. Few studies have chosen cognitive outcome as a primary endpoint. Cognitive secondary outcome measures of randomized controlled trials or their extension have been reported [99]. For instance, a positive effect of interferon beta 1b subcutaneous has been demonstrated in patients included after a CIS [100]. Another randomized clinical trial was performed for evaluating the effect on cognitive function of different types of interferon beta (Avonex, Rebif, and Betaferon) in newly diagnosed RRMS with one-year of follow-up [101]. In accordance with some previous studies focusing on the effect on interferon beta in MS [102, 103], the results suggest a positive effect on these disease-modifying drugs in preventing cognitive deterioration in MS. Encouragingly, cognitive performances have been also improved during an observational open-label study testing one monoclonal antibody in RRMS patients [104]. Moreover, fingolimod was tested in lipopolysaccharide (LPS) model in rats in order to explore the link between immune activation and cognition [105]. Indeed, the LPS was used as an agent inducing microglial cell activation and brain inflammation. Interestingly, a protective effect of fingolimod was demonstrated at different experimental levels (functional, histological, and transcriptional steps) suggesting its application in treating memory impairment in neuroinflammatory conditions.
Moreover, several symptomatic drugs have been tested to improve cognition in patients with MS, such as anticholinesterasics (donepezil, rivastigmine) and channel blockers [99]. However, no drug has shown positive results in large randomized controlled trials. Some positive results have been reported on short-term follow-up with l-amphétamine [99]. In conclusion, these studies provide insufficient data for prescribing symptomatic treatment for preventing and treating CI in patients with MS.
Cognitive Rehabilitation and Remediation
There is a lack of well-designed research studies investigating the effectiveness of cognitive rehabilitation programs in patients with MS [106, 107]. As the impairment of IPS is a key deficit in MS and has a prognostic value in this disease, its early detection and management seem to be clinically relevant and justify putting some efforts to investigate the impact of specific cognitive rehabilitation and remediation programs. Moreover, managing episodic memory is also a challenge of this type of programs and some specific studies are in progress. Besides, it is clinically relevant to focus on ecological validity of this type of rehabilitation.
Conclusion
Cognitive impairment is common in MS and could be seen in each type and stage of the disease. It affects primarily information processing speed, and episodic memory is frequently impaired too. CI has a negative impact on daily activities and in particular on vocational status of patients living with MS. Even if there is a high variability, cognitive functions tend to deteriorate over time as cumulative brain damage occurs. There is increasing evidence that CI could be due to a disconnection syndrome relative to the accumulated focal and diffuse brain damage within the white and gray matter structures. Educational level, leisure activities, and intelligence quotient contribute to cognitive reserve and have the potential to attenuate the consequences of cognitive deficits at least at the beginning of the pathology. The presence of brain compensatory mechanisms supported the development of rehabilitation and cognitive remediation programs. Longitudinal studies with long follow-up including clinical, neuropsychological, and imaging assessments are still needed to better understand the pathophysiology of cognitive impairment in both active and non-active patients with MS. One of the remaining challenge is the treatment of cognitive impairment in patients with MS, and works are in progress.
References
Langdon DW. Cognition in multiple sclerosis. Curr Opin Neurol. 2011;24:244–9.
Chiaravalloti ND, DeLuca J. Cognitive impairment in multiple sclerosis. Lancet Neurol. 2008;7:1139–51.
DeLuca J, Chelune GJ, Tulsky DS, Lengenfelder J, Chiaravalloti ND. Is speed of processing or working memory the primary information processing deficit in multiple sclerosis? J Clin Exp Neuropsychol. 2004;26:550–62.
Forn C, Belenguer A, Parcet-Ibars MA, Avila C. Information-processing speed is the primary deficit underlying the poor performance of multiple sclerosis patients in the Paced Auditory Serial Addition Test (PASAT). J Clin Exp Neuropsychol. 2008;13:1–8.
Berrigan LI, Lefevre JA, Rees LM, Berard J, Freedman MS, Walker LA. Cognition in early relapsing-remitting multiple sclerosis: consequences may be relative to working memory. J Int Neuropsychol Soc. 2013;19:938–49.
Rao SM, Leo GJ, Bernardin L, Unverzagt F. Cognitive dysfunction in multiple sclerosis. I. Frequency, patterns, and prediction. Neurology. 1991;41:685–91.
Benedict RH, Cookfair D, Gavett R, et al. Validity of the minimal assessment of cognitive function in multiple sclerosis (MACFIMS). J Int Neuropsychol Soc. 2006;12:549–58.
Brochet B. Prevalence, profile and functional impact of cognitive impairment in multiple sclerosis. In: Amato MP, editor. Cognitive impairment in multiple sclerosis. Milano: Elsevier; 2011. p. 1–8.
Peyser JM, Edwards KR, Poser CM, Filskov SB. Cognitive function in patients with multiple sclerosis. Arch Neurol. 1980;37:577–9.
Lyon-Caen O, Jouvent R, Hauser S, et al. Cognitive function in recent-onset demyelinating diseases. Arch Neurol. 1986;43:1138–41.
Truelle JL, Palisson E, Le Gall D, Stip E, Derouesne C. Intellectual and mood disorders in multiple sclerosis. Rev Neurol (Paris). 1987;143:595–601.
Deloire MS, Salort E, Bonnet M, et al. Cognitive impairment as marker of diffuse brain abnormalities in early relapsing-remitting multiple sclerosis. J Neurol Neurosurg Psychiatry. 2005;76:519–26.
Patti F, Amato M, Trojano M, et al. Cognitive impairment and its relation with disease measures in mildly disabled patients with relapsing–remitting multiple sclerosis: Baseline results from the Cognitive Impairment in Multiple Sclerosis (COGIMUS) study. Mult Scler. 2009;15:779–88.
Amato MP, Zipoli V, Goretti B, et al. Benign multiple sclerosis: cognitive, psychological and social aspects in a clinical cohort. J Neurol. 2006;253:1054–9.
Fischer M, Kunkel A, Bublak P, Faiss JH. How reliable is the classification of cognitive impairment across different criteria in early and late stages of multiple sclerosis? J Neurol Sci. 2014;343:91–9.
Feinstein A, Kartsounis LD, Miller DH, Youl BD, Ron MA. Clinically isolated lesions of the type seen in multiple sclerosis: a cognitive, psychiatric, and MRI follow up study. J Neurol Neurosurg Psychiatry. 1992;55:869–76.
Callanan MM, Logsdail SJ, Ron MA, Warrington EK. Cognitive impairment in patients with clinically isolated lesions of the type seen in multiple sclerosis. A psychometric and MRI study. Brain. 1989;112:361–74.
Pelosi L, Geesken JM, Holly M, Hayward M, Blumhardt LD. Working memory impairment in early multiple sclerosis. Evidence from an event-related potential study of patients with clinically isolated myelopathy. Brain. 1997;120:2039–58.
Achiron A, Barak Y. Cognitive impairment in probable multiple sclerosis. J Neurol Neurosurg Psychiatry. 2003;74:443–6.
Feuillet L, Reuter F, Audoin B, et al. Early cognitive impairment in patients with clinically isolated syndrome suggestive of multiple sclerosis. Mult Scler. 2007;13:124–7.
Zipoli V, Goretti B, Hakiki B, et al. Cognitive impairment predicts conversion to multiple sclerosis in clinically isolated syndromes. Mult Scler. 2010;16:62–7.
Amato MP, Hakiki B, Goretti B, et al. Association of MRI metrics and cognitive impairment in radiologically isolated syndromes. Neurology. 2012;78:309–14.
Lebrun C, Blanc F, Brassat D, Zephir H, J Seze J, CFSEP. Cognitive function in radiologically isolated syndrome. Mult Scler. 2010;16:919–25.
Comi G, Filippi M, Martinelli V, et al. Brain magnetic resonance imaging correlates of cognitive impairment in primary and secondary progressive multiple sclerosis. J Neurol Sci. 1995;132:222–7.
Foong J, Rozewicz L, Chong WK, Thompson AJ, Miller DH, Ron MA. A comparison of neuropsychological deficits in primary and secondary progressive multiple sclerosis. J Neurol. 2000;247:97–101.
Gaudino EA, Chiaravalloti ND, DeLuca J, Diamond BJ. A comparison of memory performance in relapsing-remitting, primary progressive and secondary progressive, multiple sclerosis. Neuropsychiat Neuropsychol Behav Neurol. 2001;14:32–44.
Huijbregts SC, Kalkers NF, de Sonneville LM, de Groot V, Reuling IE, Polman CH. Differences in cognitive impairment of relapsing remitting, secondary, and primary progressive MS. Neurology. 2004;63:335–9.
Wachowius U, Talley M, Silver N, Heinze HJ, Sailer M. Cognitive impairment in primary and secondary progressive multiple sclerosis. J Clin Exp Neuropsychol. 2005;27:65–77.
Potagas C, Giogkaraki E, Koutsis G, et al. Cognitive impairment in different MS subtypes and clinically isolated syndromes. J Neurol Sci. 2008;267:100–6.
Ruet A, Deloire M, Charré-Morin J, Hamel D, Brochet B. Cognitive impairment differs between primary progressive and relapsing-remitting MS. Neurology. 2013;80:1501–8.
Jennekens-Schinkel A, Laboyrie PM, Lanser JB, van der Velde EA. Cognition in patients with multiple sclerosis after four years. J Neurol Sci. 1990;99:229–47.
Kujala P, Portin R, Ruutiainen J. The progress of cognitive decline in multiple sclerosis A controlled 3-year follow-up. Brain. 1997;120:289–97.
Amato MP, Ponziani G, Siracusa G, Sorbi S. Cognitive dysfunction in early-onset multiple sclerosis: a reappraisal after 10 years. Arch Neurol. 2001;58:1602–6.
Rosti E, Hämäläinen P, Koivisto K, Hokkanen L. One-year follow-up study of relapsing-remitting MS patients’ cognitive performances: Paced Auditory Serial Addition Test’s susceptibility to change. J Int Neuropsychol Soc. 2007;13:791–8.
Denney DR, Lynch SG, Parmenter BA. A 3-year longitudinal study of cognitive impairment in patients with primary progressive multiple sclerosis: speed matters. J Neurol Sci. 2008;267:129–36.
Duque B, Sepulcre J, Bejarano B, Samaranch L, Pastor P, Villoslada P. Memory decline evolves independently of disease activity in MS. Mult Scler. 2008;14:947–53.
Amato MP, Portaccio E, Goretti B, et al. Relevance of cognitive deterioration in early relapsing–remitting MS: a 3-year follow-up study. Mult Scler. 2010;16:1474–82.
Strober LB, Rao SM, Lee JC, Fischer E, Rudick R. Cognitive impairment in multiple sclerosis: An 18 year follow-up study. Mult Scler Relat Disord. 2014;3:473–81.
Portaccio E, Amato MP. Natural history. In: Amato MP, editor. Cognitive impairment in multiple sclerosis. Milano: Elsevier; 2011. p. 29–36.
Deloire MS, Ruet A, Hamel D, Bonnet M, Dousset V, Brochet B. MRI predictors of cognitive outcome in early multiple sclerosis. Neurology. 2011;76:1161–7.
Reuter F, Zaaraoui W, Crespy L, et al. Frequency of cognitive impairment dramatically increases during the first 5 years of multiple sclerosis. J Neurol Neurosurg Psychiatry. 2011;82:1157–9.
Pardini M, Uccelli A, Grafman J, Yaldizli Ö, Mancardi G, Roccatagliata L. Isolated cognitive relapses in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2014;85:1035–7.
Smith A. Symbol Digit Modalities Test (SDMT) manual (revised). Los Angeles: Western Psychological Services; 1982.
Rao SM, The Cognitive Function Study Group of the National Multiple Sclerosis Society. A manual for the brief repeatable battery of neuropsychological tests in multiple sclerosis. Milwaukee: Medical College of Wisconsin; 1990.
Dujardin K, Sockeel P, Cabaret M, De Sèze J, Vermersch P. BCcogSEP: a French test battery evaluating cognitive functions in multiple sclerosis. Rev Neurol (Paris). 2004;160:51–62.
Benedict RH, Fischer JS, Archibald C, et al. Minimal neuropsychological assessment of MS patients: a consensus approach. Clin Neuropsychol. 2002;16:381–97.
Benedict RH, Munschauer F, Linn R, et al. Screening for multiple sclerosis cognitive impairment using a self-administered 15-item questionnaire. Mult Scler. 2003;9:95–101.
Deloire MS, Bonnet MC, Salort E, et al. How to detect cognitive dysfunction at early stages of multiple sclerosis? Mult Scler. 2006;12:445–52.
Benedict RH, Cox D, Thompson LL, Foley F, Weinstock-Guttman B, Munschauer F. Reliable screening for neuropsychological impairment in multiple sclerosis. Mult Scler. 2004;10:675–8.
Parmenter BA, Weinstock-Guttman B, Garg N, Munschauer F, Benedict RH. Screening for cognitive impairment in multiple sclerosis using the Symbol digit Modalities Test. Mult Scler. 2007;13:52–7.
Benedict RH, Duquin JA, Jurgensen S, et al. Repeated assessment of neuropsychological deficits in multiple sclerosis using the Symbol Digit Modalities Test and the MS Neuropsychological Screening Questionnaire. Mult Scler. 2008;14:940–6.
Benedict RH, Smerbeck A, Parikh R, Rodgers J, Cadavid D, Erlanger D. Reliability and equivalence of alternate forms for the Symbol Digit Modalities Test: implications for multiple sclerosis clinical trials. Mult Scler. 2012;18:1320–5.
Langdon DW, Amato MP, Boringa J, et al. Recommendations for a Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS). Mult Scler. 2012;18:891–8.
Ruet A, Deloire MS, Charré-Morin J, Hamel D, Brochet B. A new computerised cognitive test for the detection of information processing speed impairment in multiple sclerosis. Mult Scler. 2013;19:1665–72.
Weigl E. On the psychology of so-called process of abstraction. J Abnorm Soc Psychol. 1941;36:3–33.
Rossini ED, Karl MA. The Trail Makin Test A and B: a technical note on structural non-equivalence. Percept Mot Skills. 1994;78:625–6.
Zimmermann P, Fimm B. 2.1 Tests d’évaluation de l’attention. Würzelen: Psytest; 2009.
Delis DC, Kramer JH, Kaplan E, Ober BA. California verbal learning test manual: second edition, adult version. San Antonio: Psychological Corporation; 2000.
Benedict RH. Brief visuospatial memory test-revised. Professional manual. Odessa: Psychological Assessment Resources, Inc.; 1997.
Rao SM, Leo GJ, Ellington L, Nauertz T, Bernardin L, Unverzagt F. Cognitive dysfunction in multiple sclerosis. II Impact on employment and social functioning. Neurology. 1991;41:692–6.
Morrow SA, Drake A, Zivadinov R, Munschauer F, Weinstock-Guttman B, Benedict RH. Predicting loss of employment over three years in multiple sclerosis: clinically meaningful cognitive decline. Clin Neuropsychol. 2010;24:1131–45.
Ruet A, Deloire M, Hamel D, Ouallet JC, Petry K, Brochet B. Cognitive impairment, health-related quality of life and vocational status at early stages of multiple sclerosis: a 7-year longitudinal study. J Neurol. 2013;260:776–84.
Benito-León J, Morales JM, Rivera-Navarro J. Health-related quality of life and its relationship to cognitive and emotional functioning in multiple sclerosis patients. Eur J Neurol. 2002;9:497–502.
Mitchell AJ, Benito-León J, Morales González JM, Rivera-Navarro J. Quality of life and its assessment in multiple sclerosis: integrating physical and psychological components of wellbeing. Lancet Neurol. 2005;4:556–66.
Clavelou P, Auclair C, Taithe F, Gerbaud L. Quality of life in multiple sclerosis. Rev Neurol (Paris). 2009;165 Suppl 4:S123–8.
Fernández O, Baumstarck-Barrau K, Simeoni MC, Auquier P. MusiQoL study group. Patient characteristics and determinants of quality of life in an international population with multiple sclerosis: assessment using the MusiQoL and SF-36 questionnaires. Mult Scler. 2011;17:1238–49.
Baumstarck-Barrau K, Simeoni MC, Reuter F, et al. Cognitive function and quality of life in multiple sclerosis patients: a cross-sectional study. BMC Neurol. 2011;2:11–7.
Filippi M, Rocca MA, Benedict RH, et al. The contribution of MRI in assessing cognitive impairment in multiple sclerosis. Neurology. 2010;75:2121–8.
DeLuca GC, Yates RL, Beale H, Morrow SA. Cognitive impairment in multiple sclerosis: clinical. Radiol Pathol Insight Brain Pathol. 2015;25:79–98.
Rocca MA, Amato MP, De Stefano N, MAGNIMS Study Group, et al. Clinical and imaging assessment of cognitive dysfunction in multiple sclerosis. Lancet Neurol. 2015;14:302–17.
Rossi F, Giorgio A, Battalini M, et al. Relevance of brain lesion location to cognition in relapsing multiple sclerosis. Plos One. 2012;7, e44826.
Ruet A, Hamel D, Deloire MS, Charré-Morin J, Saubusse A, Brochet B. Information processing speed impairment and cerebellar dysfunction in relapsing-remitting multiple sclerosis. J Neurol Sci. 2014;347:246–50.
Cerasa A, Valentino P, Chiriaco C, et al. MR imaging and cognitive correlates of relapsing-remitting multiple sclerosis patients with cerebellar symptoms. J Neurol. 2013;260:1358–66.
Bonnet MC, Dilharreguy B, Allard M, Deloire MS, Petry KG, Brochet B. Differential cerebellar and cortical involvement according to various attentional load: role of educational level. Hum Brain Mapp. 2009;30:1133–43.
Rocca MA, Bonnet MC, Meani A, et al. Differential cerebellar functional interactions during an interference task across multiple sclerosis phenotypes. Radiology. 2012;265:864–73.
Faiss JH, Dähne D, Baum K, et al. Reduced magnetisation transfer ratio in cognitively impaired patients at the very early stage of multiple sclerosis: a prospective, multicenter, cross-sectional study. BMJ Open. 2014;4:e004409. doi:10.1136/bmjopen-2013-04409.
Dineen RA, Vilisaar J, Hlinka J, et al. Disconnection as a mechanism for cognitive dysfunction in multiple sclerosis. Brain. 2009;132:239–49.
Roosendaal SD, Geurts JJ, Vrenken H, et al. Regional DTI differences in multiple sclerosis patients. Neuroimage. 2009;44:1397–403.
Mesaros S, Rocca MA, Kacar K, et al. Diffusion tensor MRI tractography and cognitive impairment in multiple sclerosis. Neurology. 2012;78:969–75.
Audoin B, Au Duong MV, Ranjeva JP, et al. Magnetic resonance study of the influence of tissue damage and cortical reorganization on PASAT performance at the earliest stage of multiple sclerosis. Hum Brain Mapp. 2005;24:216–28.
Bonnet MC, Allard M, Dilharreguy B, Deloire M, Petry KG, Brochet B. Cognitive compensation failure in multiple sclerosis. Neurology. 2010;75:1241–8.
Hulst HE, Geurts JJ. Gray matter imaging in multiple sclerosis: what have we learned? BMC Neurol. 2011;11:153.
Calabrese M, Agosta F, Rinaldi F, et al. Cortical lesions and atrophy associated with cognitive impairment in relapsing-remitting multiple sclerosis. Arch Neurol. 2009;66:1144–50.
Sicotte NL, Kern KC, Giesser BS, et al. Regional hippocampal atrophy in multiple sclerosis. Brain. 2008;131:1134–41.
Louapre C, Perlbarg V, Garcia-Lorenzo D, et al. Brain networks disconnection in early multiple sclerosis cognitive deficits: an anatomofunctional study. Hum Brain Mapp. 2014;35:4706–17.
Sumowski JF, Chiaravalloti N, DeLuca J. Cognitive reserve protects against cognitive dysfunction in multiple sclerosis. J Clin Exp Neuropsychol. 2009;31:913–26.
Sumowski JF, Wylie GR, Deluca J, Chiaravalloti N. Intellectual enrichment is linked to cerebral efficiency in multiple sclerosis: functional magnetic resonance imaging evidence for cognitive reserve. Brain. 2010;133:362–74.
Arnett PA, Brochet B. How can cognitive reserve in multiple sclerosis inform clinical care? Neurology. 2013;80:1724–5.
Uher T, Blahova-Dusankova J, Horakova D, et al. Longitudinal MRI and neuropsychological assessment of patients with clinically isolated syndrome. J Neurol. 2014;261:1735–44.
Penny S, Khaleeli Z, Cipolotti L, Thompson A, Ron M. Early imaging predicts later cognitive impairment in primary progressive multiple sclerosis. Neurology. 2010;74:545–52.
Choi SR, Howell OW, Carassiti D, et al. Meningeal inflammation plays a role in the pathology of primary progressive multiple sclerosis. Brain. 2012;1–13.
Rovaris M, Barkhof F, Calabrese M, et al. MRI features of benign multiple sclerosis: toward a new definition of this disease phenotype. Neurology. 2009;72:1693–701.
Nocentini U, Pasqualetti P, Bonavita S, et al. Cognitive dysfunction in patients with relapsing-remitting multiple sclerosis. Mult Scler. 2006;12:77–87.
Deloire M, Ruet A, Hamel D, Bonnet M, Brochet B. Early cognitive impairment in multiple sclerosis predicts disability outcome several years later. Mult Scler. 2010;16:581–7.
Hohol MJ, Guttmann CR, Orav J, et al. Serial neuropsychological assessment and magnetic resonance imaging analysis in multiple sclerosis. Arch Neurol. 1997;54:1018–25.
De Sonneville LM, Boringa JB, Reuling IE, Lazeron RH, Adèr HJ, Polman CH. Information processing characteristics in subtypes of multiple sclerosis. Neuropsychologia. 2002;40:1751–65.
Lynch SG, Parmenter BA, Denney DR. The association between cognitive impairment and physical disability in multiple sclerosis. Mult Scler. 2005;11:469–76.
Lukas C, Minneboo A, de Groot V, et al. Early central atrophy rate predicts 5 year clinical outcome in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2010;81:1351–6.
Amato MP, Langdon D, Montalban X, et al. Treatment of cognitive impairment in multiple sclerosis: position paper. J Neurol. 2013;260(6):1452–68.
Penner IK, Stemper B, Calabrese P, et al. Effects of interferon beta-1b on cognitive performance in patients with a first event suggestive of multiple sclerosis. Mult Scler. 2012;18(10):1466–71.
Mokhber N, Azarpazhhoh A, Orouji E, et al. Cognitive dysfunction in patients with multiple sclerosis treated with different types of interferon beta: a randomized clinical trial. J Neurol Sci. 2014;342:16–20.
Fischer JS, Priore RL, Jacobs LD, Cookfair DL, Rudick RA, Herndon RM, et al. Neuropsychological effects of interferon beta-1 a in relapsing multiple sclerosis. Multiple Sclerosis Collaborative Research group. Ann Neurol. 2000;48:885–92.
Barak Y, Achiron A. Effect of interferon-beta-1 b on cognitive functions in multiple sclerosis. Eur Neurol. 2002;47:11–4.
Iaffaldano P, Viterbo RG, Paolicelli D, et al. Impact of natalizumab on cognitive performances and fatigue in relapsing multiple sclerosis: a prospective, open-label, two years observational study. PLoS One. 2012;7, e35843.
Omidbakhsh R, Rajabli B, Nasoohi S, et al. Fingolimod affects gene expression profile associated with LPS-induced memory impairment. Exp Brain Res. 2014;232:3687–96.
O'Brien AR, Chiaravalloti N, Goverover Y, Deluca J. Evidenced-based cognitive rehabilitation for persons with multiple sclerosis: a review of the literature. Arch Phys Med Rehabil. 2008;89:761–9.
Rosti-Otajärvi EM, Hämäläinen PI. Neuropsychological rehabilitation for multiple sclerosis. Cochrane Database Syst Rev. 2011;9, CD009131.
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Ruet, A. (2015). Cognitive Impairment in Multiple Sclerosis. In: Brochet, B. (eds) Neuropsychiatric Symptoms of Inflammatory Demyelinating Diseases. Neuropsychiatric Symptoms of Neurological Disease. Springer, Cham. https://doi.org/10.1007/978-3-319-18464-7_16
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